This Merit Award has permitted the opportunity to focus over the past decade on the molecular/epigenetic strategies that combinatorially regulate programs of gene transcription, that include investigation of histone demethylases, the actions of non-coding RNAs in recruiting regulatory protein complexes in control of transcriptional programs, the role of regulated nuclear architecture in transcriptional regulation and tumor translocation events, the linkage of transcription and DNA damage/repair, the role of specific phosphatases in gene regulation, regulated apoptosis/survival, and the strategies of exchanging corepressor coactivators. Under the first Specific Aim, and based on extensive preliminary data, new histone demethylases affecting cell cycle regulation will be explored and various new aspects of enhancer programming and regulation will be investigated. Under the second Specific Aim, new strategies to investigate tumor translocation by sex steroid receptors, the connection between specific demethylases and septic shock will be explored, and a new strategy for screening chemical libraries is being developed. The recent introduction of powerful new technologies, including next-generation sequencing, has permitted us to generate preliminary data designed to uncover previously- unsuspected aspects of epigenetic regulation of transcription, with particular relevance to translational aspects of common disease including breast and prostate cancer and cytokine storm syndromes, translational areas that represent important research objectives in this Competitive Renewal. We propose specific areas of investigation based on several novel and promising new technologies we are developing under this Grant that will be of broad utility to the scientific community, centered on key, unanswered questions concerning gene regulation by nuclear receptors. We propose to vigorously pursue these fundamental issues in order to accelerate the discovery of as yet unknown putative tumor translocation events in breast cancer, and to complete the development of new, powerful strategies including a new multiplexed screen to identify new approaches to intervene in these regulatory and pathological events. PUBLIC HEALTH RELEVANCE: Nuclear Receptors regulate key aspects of development, homeostasis and provide protection against many inflammatory diseases and also provide ideal models to reveal basic molecular mechanisms for genome-wide transcriptional programs. New technologies are proposed that will help us define the regulatory epigenetic landscape in metazoans. The translational aspect of this proposal studies focus on the clinically important diseases of - breast cancer, prostate cancer, and condition of septic-shock, three all-too-prevalent causes of mortality in this country and in the world and by initiating new technologies, including a novel chemical library screening technology, we hope to uncover novel therapeutic leads, as well as to provide central insights into nuclear receptor function.